Targeted siRNA nanotechnology for intravesical treatment of urologicaldiseases

靶向 siRNA 纳米技术用于膀胱内治疗泌尿系统疾病

基本信息

  • 批准号:
    7938678
  • 负责人:
  • 金额:
    $ 48.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2012-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Our Broad Challenge is to develop enabling technologies for the prevention and treatment of diseases affecting the bladder. The Proof of Concept that we are testing is that intravesical instillation of small interference RNA (siRNA) packaged in biodegradable nanospheres provides wide opportunities for the treatment of urologic diseases including transitional cell carcinoma of the bladder (TCC), interstitial cystitis (IC), overactive bladder, and detrusor hyperreflexia. Because of their robust, gene selective silencing of target protein expression, siRNA oligonucleotides are an attractive therapeutic option with high selectivity and specificity and minimal toxicity to neighboring cells. siRNAs, however, have a relatively short half-life and thus we will address the technical challenges of stabilization and intravesical delivery of siRNAs. To achieve this goal, we plan to create and test clinically viable, non-viral nanosphere siRNA complexes that are intravesically instilled for treatment of diseases of the urinary tract. This past year, in collaboration with Drs. W. Mark Saltzman and Kim Woodrow of the Yale University Department of Bioengineering, we have shown that antennapedia (AP), a Drosophila transcription factor that facilitates uptake of peptides and oligonucleotides into mammalian cells, when complexed with PLGA nanoparticles (AP-PLGA) adheres effectively to T-24 bladder cancer cells, and slowly releases complexed siRNA over 10 days in amounts sufficient to downregulate intracellular target mRNA and protein. Conversely, naked survivin and VEGF siRNA are stable for only a few hours. We have complexed two siRNAs with AP-PLGA, survivin siRNA and VEGF siRNA, both with relevance in urological diseases. The Inhibitor of Apoptosis (IAP), survivin, is not detected in normal urothelium and its expression in bladder cancer correlates with poor prognosis. The angiogenic factor, VEGF is overexpressed in TCC and may play an important role in the pathogenesis of TCC and interstitial cystitis. We have shown that these survivin siRNA-AP-PLGA and VEGF siRNA-AP-PLGA are released into the T-24 cells and down-regulate targeted mRNA and protein. Furthermore, VEGF siRNA-AP-PLGA downregulates VEGF levels in normal human urothelium. We now plan to: 1) develop and test a number of nanoparticle controlled release systems containing targeting proteins that will stabilize and deliver siRNAs and drugs, to test their physicochemical properties (materials testing), and the capacity of the nanoparticles to release siRNA efficiently from the nanospheres to an intracellular target site; 2) move from an in vitro to an in vivo system and test in a whole animal the ability of human targeted encapsulated siRNAs to reduce target protein and mRNA and cell/tumor growth; and 3) test whether combinations of encapsulated siRNAs and/or histone deacetylase inhibitors (HDACIs) more effectively reduce tumor burden, the time to onset, rate of occurrence and mortality compared to individual encapsulated siRNAs in a nitrosamine induced bladder cancer model. The ultimate challenge is to design more effective intravesical instillation protocols for treatment of common urological diseases including bladder cancer, overactive bladder and IC using siRNAs encapsulated in microspheres to increase their stability and prolong their efficacy. Standard chemotherapeutic treatment options for urological diseases including bladder cancer, overactive bladder and interstitial cystitis may cause undesirable side effects or may be ineffective. Small interference RNA (siRNA) can specifically and sensitively degrade RNA messages and thus reduce levels of the proteins synthesized from the specific mRNAs that may play a role in disease development. In order to exploit the therapeutic potential of these siRNAs, which are short lived and easily degraded, we have designed strategies to stabilize and test them. We plan to encapsulate the siRNAs in polymer nanoparticles which will release the siRNA over days to weeks. We also will add peptides that will target the nanoparticles to specific cells within the bladder. These siRNA polymers will be instilled into the bladder as a treatment for urological diseases. Because more than one siRNA can be encapsulated and targeted in the same nanoparticle, we can downregulate more than one urologic disease pathway with the same nanoparticles. Our first test of these nanoparticles will use a mouse model of bladder cancer. Thus, we can determine the therapeutic potential of siRNA for treatment of urologic diseases.
描述(由申请人提供):我们的广泛挑战是开发用于预防和治疗影响膀胱的疾病的技术。我们正在测试的概念证明是,包装在可生物降解纳米球中的小干扰RNA(siRNA)的膀胱内滴注为泌尿系统疾病的治疗提供了广泛的机会,包括膀胱移行细胞癌(TCC)、间质性膀胱炎(IC)、膀胱过度活动症和逼尿肌反射亢进。由于它们对靶蛋白表达的稳健的基因选择性沉默,siRNA寡核苷酸是具有高选择性和特异性以及对邻近细胞的最小毒性的有吸引力的治疗选择。然而,siRNA具有相对短的半衰期,因此我们将解决siRNA的稳定化和膀胱内递送的技术挑战。为了实现这一目标,我们计划创建和测试临床上可行的非病毒纳米球siRNA复合物,其被膀胱内滴注用于治疗尿路疾病。在过去的一年里,与W博士合作。耶鲁大学生物工程系的Mark Saltzman和Kim Woodrow,我们已经证明,当与PLGA纳米颗粒(AP-PLGA)复合时,触角足(AP),一种促进哺乳动物细胞摄取肽和寡核苷酸的果蝇转录因子,有效地粘附于T-24膀胱癌细胞,并在10天内以足以下调细胞内靶mRNA和蛋白质的量缓慢释放复合的siRNA。相反,裸存活素和VEGF siRNA仅稳定几个小时。我们已经将两种siRNA与AP-PLGA复合,生存素siRNA和VEGF siRNA,两者都与泌尿系统疾病相关。凋亡抑制因子Survivin在正常尿路上皮中未检测到,其在膀胱癌中的表达与不良预后相关。血管生成因子VEGF在膀胱移行细胞癌中表达增高,可能在膀胱移行细胞癌和间质性膀胱炎的发病机制中起重要作用。我们已经表明,这些生存素siRNA-AP-PLGA和VEGF siRNA-AP-PLGA被释放到T-24细胞中,并下调靶向mRNA和蛋白质。此外,VEGF siRNA-AP-PLGA下调正常人尿路上皮中的VEGF水平。我们现在计划:1)开发和测试一些含有靶向蛋白的纳米颗粒控释系统,这些靶向蛋白将稳定和递送siRNA和药物,以测试它们的物理化学性质(材料测试),以及纳米颗粒从纳米球有效释放siRNA到细胞内靶位点的能力; 2)从体外系统转移到体内系统,并在整个动物中测试人靶向的包封siRNA减少靶蛋白和mRNA以及细胞/肿瘤生长的能力;和3)测试在亚硝胺诱导的膀胱癌模型中,与单独的包封siRNA相比,包封siRNA和/或组蛋白脱乙酰酶抑制剂(HDACI)的组合是否更有效地降低肿瘤负荷、发病时间、发生率和死亡率。最终的挑战是设计更有效的膀胱内滴注方案,用于治疗常见的泌尿系统疾病,包括膀胱癌,膀胱过度活动症和IC,使用封装在微球中的siRNA来增加其稳定性并延长其功效。泌尿系统疾病(包括膀胱癌、膀胱过度活动症和间质性膀胱炎)的标准化疗治疗选项可能会导致不良副作用或可能无效。小干扰RNA(siRNA)可以特异性和敏感地降解RNA信息,从而降低由特定mRNA合成的蛋白质的水平,这些蛋白质可能在疾病发展中起作用。为了开发这些siRNA的治疗潜力,这些siRNA寿命短且容易降解,我们设计了稳定和测试它们的策略。我们计划将siRNA封装在聚合物纳米颗粒中,这些聚合物纳米颗粒将在几天到几周内释放siRNA。我们还将添加肽,使纳米颗粒靶向膀胱内的特定细胞。这些siRNA聚合物将被注入膀胱作为泌尿系统疾病的治疗。因为不止一种siRNA可以被封装并靶向在同一纳米颗粒中,所以我们可以用相同的纳米颗粒下调不止一种泌尿系统疾病途径。我们对这些纳米颗粒的第一次测试将使用膀胱癌小鼠模型。因此,我们可以确定siRNA用于治疗泌尿系统疾病的治疗潜力。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ROBERT M WEISS其他文献

ROBERT M WEISS的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ROBERT M WEISS', 18)}}的其他基金

Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
  • 批准号:
    10216324
  • 财政年份:
    2018
  • 资助金额:
    $ 48.64万
  • 项目类别:
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
  • 批准号:
    10452547
  • 财政年份:
    2018
  • 资助金额:
    $ 48.64万
  • 项目类别:
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
  • 批准号:
    9977238
  • 财政年份:
    2018
  • 资助金额:
    $ 48.64万
  • 项目类别:
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
  • 批准号:
    9762207
  • 财政年份:
    2018
  • 资助金额:
    $ 48.64万
  • 项目类别:
High-Resolution Research Ultrasound
高分辨率研究超声
  • 批准号:
    8824742
  • 财政年份:
    2015
  • 资助金额:
    $ 48.64万
  • 项目类别:
Research Ultrasound Imaging Upgrades
研究超声成像升级
  • 批准号:
    7784169
  • 财政年份:
    2010
  • 资助金额:
    $ 48.64万
  • 项目类别:
Targeted siRNA nanotechnology for intravesical treatment of urologicaldiseases
靶向 siRNA 纳米技术用于膀胱内治疗泌尿系统疾病
  • 批准号:
    7832079
  • 财政年份:
    2009
  • 资助金额:
    $ 48.64万
  • 项目类别:
Encapsulated siRNAs for treatment of urological disease
用于治疗泌尿系统疾病的封装 siRNA
  • 批准号:
    7481032
  • 财政年份:
    2007
  • 资助金额:
    $ 48.64万
  • 项目类别:
Encapsulated siRNAs for treatment of urological disease
用于治疗泌尿系统疾病的封装 siRNA
  • 批准号:
    7238990
  • 财政年份:
    2007
  • 资助金额:
    $ 48.64万
  • 项目类别:
CARDIOVASCULAR PHENOTYPING IN MICE
小鼠心血管表型分析
  • 批准号:
    6846333
  • 财政年份:
    2003
  • 资助金额:
    $ 48.64万
  • 项目类别:

相似海外基金

An innovative, AI-driven prehabilitation platform that increases adherence, enhances post-treatment outcomes by at least 50%, and provides cost savings of 95%.
%20创新、%20AI驱动%20康复%20平台%20%20增加%20依从性、%20增强%20治疗后%20结果%20by%20at%20至少%2050%、%20和%20提供%20成本%20节省%20of%2095%
  • 批准号:
    10057526
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
    Grant for R&D
Improving Repositioning Adherence in Home Care: Supporting Pressure Injury Care and Prevention
提高家庭护理中的重新定位依从性:支持压力损伤护理和预防
  • 批准号:
    490105
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
    Operating Grants
I-Corps: Medication Adherence System
I-Corps:药物依从性系统
  • 批准号:
    2325465
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
    Standard Grant
Unintrusive Pediatric Logging Orthotic Adherence Device: UPLOAD
非侵入式儿科记录矫形器粘附装置:上传
  • 批准号:
    10821172
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
Nuestro Sueno: Cultural Adaptation of a Couples Intervention to Improve PAP Adherence and Sleep Health Among Latino Couples with Implications for Alzheimer’s Disease Risk
Nuestro Sueno:夫妻干预措施的文化适应,以改善拉丁裔夫妇的 PAP 依从性和睡眠健康,对阿尔茨海默病风险产生影响
  • 批准号:
    10766947
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
CO-LEADER: Intervention to Improve Patient-Provider Communication and Medication Adherence among Patients with Systemic Lupus Erythematosus
共同领导者:改善系统性红斑狼疮患者的医患沟通和药物依从性的干预措施
  • 批准号:
    10772887
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
Pharmacy-led Transitions of Care Intervention to Address System-Level Barriers and Improve Medication Adherence in Socioeconomically Disadvantaged Populations
药房主导的护理干预转型,以解决系统层面的障碍并提高社会经济弱势群体的药物依从性
  • 批准号:
    10594350
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
Antiretroviral therapy adherence and exploratory proteomics in virally suppressed people with HIV and stroke
病毒抑制的艾滋病毒和中风患者的抗逆转录病毒治疗依从性和探索性蛋白质组学
  • 批准号:
    10748465
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
Improving medication adherence and disease control for patients with multimorbidity: the role of price transparency tools
提高多病患者的药物依从性和疾病控制:价格透明度工具的作用
  • 批准号:
    10591441
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
Development and implementation of peer-facilitated decision-making and referral support to increase uptake and adherence to HIV pre-exposure prophylaxis in African Caribbean and Black communities in Ontario
制定和实施同行协助决策和转介支持,以提高非洲加勒比地区和安大略省黑人社区对艾滋病毒暴露前预防的接受和依从性
  • 批准号:
    491109
  • 财政年份:
    2023
  • 资助金额:
    $ 48.64万
  • 项目类别:
    Fellowship Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了